tbuckley/cabot-search huggingface dataset:
Autoimmune Neutropenias: Update on Clinical and Biological Features in Children and Adults
Authors: Francesca Fioredda, Carlo Dufour, Petter Höglund, Helen A Papadaki, Jan Palmblad
Journal: HemaSphere (2022)

The definition of autoimmune neutropenias (AIN) has been based on the demonstration of autoantibodies directed to various epitopes on blood neutrophils. However, this definition is probably too limited and excludes neutropenias (NPs) with a negative autoantibody test but with other phenomena that indicate an underlying autoimmune process. Examples of such AINs may be complete or incomplete systemic lupus erythematosus or other autoimmune diseases where NP is common but patients may not fulfill formal diagnostic criteria for a rheumatic disease. Recently, various inherited immune-dysregulation syndromes, such as those related to variants in, for example, TACI , BAFFR , ACKR1/DARC , LRBA , CTLA 4 genes, with dysregulated B- and T-lymphocyte functions, have been associated with concomitant AINs. Cellular immune mechanisms may also play a prominent role in the development of NP, in the presence or not of autoantibodies, in cases of large granular lymphocyte syndromes of T- and NK-cell types or in chronic idiopathic NP, particularly in adults with T-cell clonal populations. The course of AIN may differ according to age, being transient and rather uncomplicated in children, and chronic with treatment requirement in adolescents and adults. This review discusses current knowledge of AINs, including diagnostic procedures, treatments, and prognosis.
Analysis of the T-cell repertoire and transcriptome identifies mechanisms of regulatory T-cell suppression of GVHD
Authors: Juliane K. Lohmeyer, Toshihito Hirai, Mustafa Turkoz, Stephane Buhler, Teresa Lopes Ramos, Natalie Köhler, Jeanette Baker, Astrid Melotti, Ingrid Wagner, Amandine Pradier, Sisi Wang, Xuhuai Ji, Simone Becattini, Jean Villard, Doron Merkler, Yves Chalandon, Robert S. Negrin, Federico Simonetta
Journal: Blood (2022)
Association Between Antiepileptic Drugs and Incident Parkinson Disease
Authors: Daniel Belete, Benjamin M. Jacobs, Cristina Simonet, Jonathan P. Bestwick, Sheena Waters, Charles R. Marshall, Ruth Dobson, Alastair J. Noyce
Journal: JAMA Neurology (2022)

Importance Recent studies have highlighted an association between epilepsy and Parkinson disease (PD). The role of antiepileptic drugs (AEDs) has not been explored. Objective To investigate the association between AEDs and incident PD. Design, Setting, and Participants This nested case-control study started collecting data from the UK Biobank (UKB) in 2006, and data were extracted on June 30, 2021. Individuals with linked primary care prescription data were included. Cases were defined as individuals with a Hospital Episode Statistics (HES)–coded diagnosis of PD. Controls were matched 6:1 for age, sex, race and ethnicity, and socioeconomic status. Prescription records were searched for AEDs prescribed prior to diagnosis of PD. The UKB is a longitudinal cohort study with more than 500 000 participants; 45% of individuals in the UKB have linked primary care prescription data. Participants living in the UK aged between 40 and 69 years were recruited to the UKB between 2006 and 2010. All participants with UKB-linked primary care prescription data (n = 222 106) were eligible for enrollment in the study. Individuals with only a self-reported PD diagnosis or missing data for the matching variables were excluded. In total, 1477 individuals were excluded; 49 were excluded due to having only self-reported PD, and 1428 were excluded due to missing data. Exposures Exposure to AEDs (carbamazepine, lamotrigine, levetiracetam, and sodium valproate) was defined using routinely collected prescription data derived from primary care. Main Outcomes and Measures Odds ratios and 95% CIs were calculated using adjusted logistic regression models for individuals prescribed AEDs before the first date of HES-coded diagnosis of PD. Results In this case-control study, there were 1433 individuals with an HES-coded PD diagnosis (cases) and 8598 controls in the analysis. Of the 1433 individuals, 873 (60.9%) were male, 1397 (97.5%) had their race and ethnicity recorded as White, and their median age was 71 years (IQR, 65-75 years). An association was found between AED prescriptions and incident PD (odds ratio, 1.80; 95% CI, 1.35-2.40). There was a trend for a greater number of prescription issues and multiple AEDs being associated with a greater risk of PD. Conclusions and Relevance This study, the first to systematically look at PD risk in individuals prescribed the most common AEDs, to our knowledge, found evidence of an association between AEDs and incident PD. With the recent literature demonstrating an association between epilepsy and PD, this study provides further insights.
The Novel Prognostic Index Model of Combining Circulating Tumor DNA and PINK-E Predicts the Clinical Outcomes for Newly Diagnosed Extranodal NK/T-cell Lymphoma
Authors: Dezhi Huang, Qiong Li, Xinlei Li, Naya Ma, Yishuo Duan, Lidan Zhu, Jiali Li, Qin Wen, Lei Gao, Cheng Yang, Lingyi Rao, Li Gao, Xi Zhang, Jun Rao
Journal: HemaSphere (2022)

Extranodal NK/T-cell lymphoma (ENKTL) is a highly aggressive and heterogeneous disease with poor clinical outcome. Our previous work had demonstrated that circulating tumor DNA (ctDNA) analyses were feasible in ENKTL, and dynamic tracing of ctDNA could be used to monitor the disease status. However, the prognostic value of ctDNA in ENKTL has not been fully investigated. Patients with newly diagnosed ENKTL from February 2017 to December 2021 (n = 70) were enrolled. The pretreatment ctDNA concentration (hGE/mL) was measured. The prognostic value of ctDNA, international prognostic index (IPI), Korean prognostic index (KPI), PINK-E, and the combination of PINK-E and ctDNA (PINK-EC) were investigated in our cohort. The IPI and PINK-E risk categories had a significant difference in progression-free survival (PFS) and overall survival (OS) between the low-risk and intermediate-risk groups. The KPI risk category had a difference in PFS and OS between the intermediate-risk and high-risk groups. Furthermore, integrating ctDNA into the PINK-E model could overcome the shortcomings of other prognostic models, which could significantly distinguish the different-risk groups. Overall, our results demonstrated that PINK-EC showed a superior prognostic prediction value and stability compared with IPI, KPI, and PINK-E. The integration of molecular features of the tumor into classic risk categories might better characterize a high-risk group where novel treatment approaches are most needed.
Minimal important difference in childhood interstitial lung diseases
Authors: Matthias Griese, Nicolaus Schwerk, Julia Carlens, Martin Wetzke, Nagehan Emiralioğlu, Nural Kiper, Joanna Lange, Katarzyna Krenke, Elias Seidl
Journal: Thorax (2022)

Background Monitoring disease progression in childhood interstitial lung diseases (chILD) is essential. No information for the minimal important difference (MID), which is defined as the smallest change in a parameter that is perceived as important prompting a clinician to change the treatment, is available. We calculated MIDs for vital signs (respiratory rate, peripheral oxygen saturation in room air, Fan severity score) and health-related quality of life (HrQoL) scores. Methods This study used data from the Kids Lung Register, which is a web-based management platform that collects data of rare paediatric lung disorders with a focus on chILD. Data of vital signs and HrQoL scores (Health Status Questionnaire, chILD-specific questionnaire and PedsQL V.4.0) were collected. MIDs were calculated according to distribution-based (one-third SD) and anchor-based methods (using forced expiratory volume in 1 s and forced vital capacity) as anchors. Results Baseline data of 774 children were used to calculate the following MIDs: respiratory rate 1.3 (z-score), O 2 saturation in room air 3.0%, Fan severity score 0.2–0.4, Health Status Questionnaire 0.4–0.8, chILD-specific questionnaire 4.4%–8.2%, physical health summary score 7.8%–8.9%, psychosocial health summary score 3.4%–6.9% and total score 5.1%–7.4%. Results of the responsiveness analysis generally agreed with the MIDs calculated. Conclusions For the first time, we provide estimates of MIDs for vital signs and HrQoL scores in a large cohort of chILD using different methods.
Mitotic count is prognostic in IDH mutant astrocytoma without homozygous deletion of CDKN2A/B. Results of consensus panel review of EORTC trial 26053 (CATNON) and EORTC trial 22033-26033
Authors: Johan M Kros, Elisabeth Rushing, Aimé L Uwimana, Aurelio Hernández-Laín, Alex Michotte, Maysa Al-Hussaini, Franck Bielle, Christian Mawrin, Gianluca Marucci, C Mircea S Tesileanu, Roger Stupp, Brigitta Baumert, Martin van den Bent, Pim J French, Thierry Gorlia
Journal: Neuro-Oncology (2022)

Gliomas with IDH1/2 mutations without 1p19q codeletion have been identified as the distinct diagnostic entity of IDH mutant astrocytoma (IDHmut astrocytoma). Homozygous deletion of Cyclin-dependent kinase 4 inhibitor A/B (CDKN2A/B) has recently been incorporated in the grading of these tumors. The question of whether histologic parameters still contribute to prognostic information on top of the molecular classification, remains unanswered. Here we evaluated consensus histologic parameters for providing additional prognostic value in IDHmut astrocytomas.
Anticoagulant Therapy for Cancer-Associated Thrombosis
Authors: Shuchi Gulati, Mark H. Eckman
Journal: Annals of Internal Medicine (2022)

Direct oral anticoagulants (DOACs) offer an alternative to low-molecular-weight heparin (LMWH) and warfarin for treating cancer-associated thrombosis (CAT).To determine the cost and effectiveness of DOACs versus LMWH.Cohort-state transition decision analytic model.Network meta-analysis comparing DOACs versus LMWH.Adult patients with cancer at the time they develop thrombosis.Lifetime.Health care sector.Strategies of 1) enoxaparin, 2) apixaban, 3) edoxaban, and 4) rivaroxaban for treatment of CAT.Incremental cost-effectiveness ratio (ICER) in 2022 U.S. dollars per quality-adjusted life-year (QALY) gained.In the base-case scenario, using drug prices from the U.S. Department of Veterans Affairs Federal Supply Schedule, apixaban dominated enoxaparin and edoxaban by being less costly and more effective. Rivaroxaban was slightly more effective than apixaban, with an ICER of $493 246. In a scenario analysis using "real-world" drug prices from GoodRx, rivaroxaban was cost-effective with an ICER of $50 053 per QALY.Results were highly sensitive to monthly drug costs. Probabilistic sensitivity analyses showed that at a willingness-to-pay threshold of $50 000 per QALY, apixaban was preferred in 80% of simulations. However, sensitivity analyses also demonstrated that apixaban only remained cost-effective if monthly medication costs were below $530. Above this, rivaroxaban became cost-effective.An assumption was made that patients would continue anticoagulation indefinitely unless they suffered a major bleed. Nonmedical costs such as patient and caregiver loss of productivity were not accounted for, and long-term thrombotic complications were not explicitly modeled.The 3 DOACs are more effective and more cost-effective than LMWH. The most cost-effective DOAC depends on the relative cost of each of these agents. These are important considerations for treating physicians and health policymakers.None.
Association of change in metabolic syndrome status with altered risk of incident gout: comment on the article by Eun et al
Authors: Gang Wang, Ning Zhuo, Mei Tang, Leixi Xue, Zhichun Liu
Journal: Arthritis & Rheumatology (2022)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Neutrophil Extracellular Trap–Borne Elastase Prevents Inflammatory Relapse in Intercritical Gout
Authors: Lei Liu, Lizhen Shan, Han Wang, Christine Schauer, Janina Schoen, Lingjiang Zhu, Ci Lu, Zitao Wang, Yu Xue, Huaxiang Wu, Martin Herrmann
Journal: Arthritis & Rheumatology (2022)

Objective Gout flares that occur during urate‐lowering therapy (ULT) are typically related to the shrinkage of tophi due to aggregated neutrophil extracellular traps (NETs) that have captured monosodium urate crystals in the tissues. The present study was undertaken to analyze the blocking effect of α 1 ‐antitrypsin on neutrophil elastase, and it was found that α 1 ‐antitrypsin induced rapid inflammation in the presence of unstable tophi. Methods Cell‐free DNA levels in serum samples were compared between patients who experienced a varying number of gout flares. We investigated whether cell‐free DNA in serum samples and α 1 ‐antitrypsin could be altered after the initiation of ULT. In mice, an injection of monosodium urate monohydrate (MSU) crystals was used to form a mimic of tophi in the peritoneal cavity, which was then analyzed using immunofluorescence staining. Finally, we investigated the relapse of inflammation by analyzing the levels of α 1 ‐antitrypsin in 2 kinds of artificial tophi and in tophus‐bearing mice. Results Levels of cell‐free DNA in serum samples correlated with the number of flares experienced by patients with tophaceous gout. ULT induced an increase in cell‐free DNA in the serum of patients with tophi. Increases in levels of α 1 ‐antitrypsin were seen in patients with tophi who received ULT. Chalk‐like tophi removed from the peritoneal cavity of mice after MSU crystals induced inflammation showed abundant coexpression of interleukin‐1β (IL‐1β) and IL‐6–associated NETs. A relapse in inflammation was induced by α 1 ‐antitrypsin during the spontaneous resolution of MSU crystal–induced peritonitis. We observed that α 1 ‐antitrypsin blocks cytokine degradation by neutrophil elastase during the resolution phase of tophi. Conclusion ULT causes shrinkage of the tophi reflected by an increase in the levels of cell‐free DNA in serum. In the resolution phase of tophi in mice, NET‐associated neutrophil elastase degrades proinflammatory cytokines and, thus, ameliorates inflammation.
Amelioration of Autoimmunity in a Lupus Mouse Model by Modulation of <scp>T‐Bet</scp>–Promoted Energy Metabolism in Pathogenic Age/<scp>Autoimmune‐Associated</scp> B Cells
Authors: Xiaxia Han, Shuangshuang Gu, Soon‐Min Hong, Yang Jiang, Jinsong Zhang, Chao Yao, Zhihua Yin, Zhizhong Ye, Huihua Ding, Sheng Chen, Dai Dai, Nan Shen
Journal: Arthritis & Rheumatology (2022)

Emerging evidence indicates that a distinct CD11c+T-bet+ B cell subset, termed age/autoimmune-associated B cells (ABCs), is the major pathogenic autoantibody producer in lupus. Human lupus is associated with significant metabolic alterations, but how ABCs orchestrate their typical transcription factors and metabolic programs to meet specific functional requirements is unclear. We undertook this study to characterize the metabolism of ABCs and to identify the regulators of their metabolic pathways in an effort to develop new therapies for ABC-mediated autoimmunity.We developed a T-bet-tdTomato reporter mouse strain to trace live T-bet+ B cells and adoptively transferred CD4+ T cells from bm12 mice to induce lupus. We next sorted CD11c+tdTomato+ B cells and conducted RNA sequencing and an extracellular flux assay. A metabolic restriction to constrain ABC formation was tested in human and mouse B cells. We used a bm12-induced lupus mouse model to conduct the metabolic intervention.ABCs exhibited a hypermetabolic state with enhanced glycolytic capacity. The increased glycolytic rate in ABCs was promoted by interferon-γ (IFNγ) signaling. T-bet, a downstream transcription factor of IFNγ, regulated the gene program of the glycolysis pathway in ABCs by repressing the expression of Bcl6. Functionally, glycolysis restriction could impair ABC formation. The engagement of glycolysis promoted survival and terminal differentiation of antibody-secreting cells. Administration of a glycolysis inhibitor ameliorated ABC accumulation and autoantibody production in the lupus-induced bm12 mouse model.T-bet can couple immune signals and metabolic programming to establish pathogenic ABC formation and functional capacities. Modulation of ABCs favored a metabolic program that could be a novel therapeutic approach for lupus.
The <scp>NLRP3</scp> Conundrum
Authors: James T. Rosenbaum, Tejpal Gill, Tammy M. Martin
Journal: Arthritis & Rheumatology (2022)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Elderly Patients with Hepatocellular Carcinoma benefit from Liver Transplantation as much as younger ones
Authors: Jens Mittler, Stefan Heinrich, Martina Koch, Maria Hoppe-Lotichius, Ali Hadian, Arndt Weinmann, Roman Kloeckner, Peter Robert Galle, Hauke Lang
Journal: Liver Cancer (2022)

Introduction: The literature on liver transplantation (LT) for cirrhosis-associated hepatocellular carcinoma (cirr-HCC) in elderly patients (≥65 years of age) is scarce. The aim of this study was therefore to analyze the outcome after LT for cirr-HCC in elderly patients in our single-center experience. Methods: All consecutive patients who underwent LT for cirr-HCC at our center were identified from our prospectively collected LT database and stratified into an elderly (≥65 years) and a younger (&lt;65 years) cohort. Perioperative mortality as well as Kaplan-Meier estimations of overall (OS) and recurrence-free survival (RFS) were compared between age strata. A subgroup analysis was performed for patients with HCC only inside Milan criteria. For further oncological comparison, outcome in the subgroup of elderly LT recipients with HCC inside Milan was also compared to a group of elderly patients undergoing liver resection for cirr-HCC inside Milan extracted from our institutional liver resection database. Results: Out of 369 consecutive patients with cirr-HCC who underwent LT between 1998 and 2022 at our center, we identified 97 elderly (with a subgroup of 14 septuagenarians) and 272 younger LT patients. 5- and 10-year OS in elderly compared to younger LT patients was 63% and 52% versus 63% and 46% (p = 0.67), respectively, while 5- and 10-year RFS was 58% and 49% versus 58% and 44% (p = 0.69). 5-/10-year OS and RFS in 50 elderly LT recipients with HCC inside Milan were 68%/55% and 62%/54%, respectively, which compared to 46%/38% (p = 0.07) and 26%/14% (p &lt; 0.0001) in elderly patients after liver resection for cirr-HCC inside Milan. Conclusion: Our results in almost 100 elderly patients after LT for cirr-HCC show that older age per se should not be considered a contraindication to LT and that selected elderly patients older than 65 and even 70 years benefit from LT as much as younger ones.
Coordinated neurostimulation promotes circuit rewiring and unlocks recovery after spinal cord injury
Authors: Valérie Van Steenbergen, Laura Burattini, Michelle Trumpp, Julie Fourneau, Almir Aljović, Maryam Chahin, Hanseul Oh, Marta D’Ambra, Florence M. Bareyre
Journal: The Journal of Experimental Medicine (2022)

Functional recovery after incomplete spinal cord injury depends on the effective rewiring of neuronal circuits. Here, we show that selective chemogenetic activation of either corticospinal projection neurons or intraspinal relay neurons alone led to anatomically restricted plasticity and little functional recovery. In contrast, coordinated stimulation of both supraspinal centers and spinal relay stations resulted in marked and circuit-specific enhancement of neuronal rewiring, shortened EMG latencies, and improved locomotor recovery.
Amino acid availability acts as a metabolic rheostat to determine the magnitude of ILC2 responses
Authors: Suzanne H. Hodge, Maria Z. Krauss, Irem Kaymak, James I. King, Andrew J.M. Howden, Gordana Panic, Richard K. Grencis, Jonathan R. Swann, Linda V. Sinclair, Matthew R. Hepworth
Journal: The Journal of Experimental Medicine (2022)

Group 2 innate lymphoid cells (ILC2) are functionally poised, tissue-resident lymphocytes that respond rapidly to damage and infection at mucosal barrier sites. ILC2 reside within complex microenvironments where they are subject to cues from both the diet and invading pathogens—including helminths. Emerging evidence suggests ILC2 are acutely sensitive not only to canonical activating signals but also perturbations in nutrient availability. In the context of helminth infection, we identify amino acid availability as a nutritional cue in regulating ILC2 responses. ILC2 are found to be uniquely preprimed to import amino acids via the large neutral amino acid transporters Slc7a5 and Slc7a8. Cell-intrinsic deletion of these transporters individually impaired ILC2 expansion, while concurrent loss of both transporters markedly impaired the proliferative and cytokine-producing capacity of ILC2. Mechanistically, amino acid uptake determined the magnitude of ILC2 responses in part via tuning of mTOR. These findings implicate essential amino acids as a metabolic requisite for optimal ILC2 responses within mucosal barrier tissues.
A deep-learning model for transforming the style of tissue images from cryosectioned to formalin-fixed and paraffin-embedded
Authors: Kutsev Bengisu Ozyoruk, Sermet Can, Berkan Darbaz, Kayhan Başak, Derya Demir, Guliz Irem Gokceler, Gurdeniz Serin, Uguray Payam Hacisalihoglu, Emirhan Kurtuluş, Ming Y. Lu, Tiffany Y. Chen, Drew F. K. Williamson, Funda Yılmaz, Faisal Mahmood, Mehmet Turan
Journal: Nature Biomedical Engineering (2022)
Author Correction: Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction
Authors: Marc Schneeberger, Nicola L. Brice, Kyle Pellegrino, Luca Parolari, Jordan T. Shaked, Keith J. Page, François Marchildon, Douglas W. Barrows, Thomas S. Carroll, Thomas Topilko, Victoria M. Mulligan, Robert Newman, Kevin Doyle, Roland Bürli, Daniel F. Barker, Angela Glen, María José Ortuño, Alexander R. Nectow, Nicolas Renier, Paul Cohen, Mark Carlton, Nathaniel Heintz, Jeffrey M. Friedman
Journal: Nature Metabolism (2022)